The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same. These advantages have been attained by a wide variety of methods. For example, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or of natural origin. A few contain both synthetic and non-synthetic material. However, some of the systems require special process and production equipment, and in addition some off these systems are susceptible to variable drug release.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements.
For the most part, the release rate of oral delivery systems have been classified according to the mechanism of release, such as zero order, first order, second order, pseudo-first order, and the like, although many pharmaceutical compounds release medicament via other, complicated mechanisms.
First order mechanisms refer to situations where the reaction rate is dependent on the concentration of the reacting substance (and therefore is dependent on the first power of the reactant). In such mechanisms, the substance decomposes directly into one or more products.
Second order mechanisms occur when the experimentally determined rate of reaction is proportional to the concentration of each of two reactants, or to the second power of the concentration of one reactant.
Pseudo first order reactions are generally defined as second order reactions which behave as though they are governed by a first order mechanism, and occur, for example, when the amount of one reacting material is manipulated by being present in great excess or being maintained at a constant concentration as compared to the other substance. In such circumstances, the reaction rate is determined by the manipulated substance.
Zero order mechanisms refer to situations where the reaction rate is independent of the concentration of the reacting substance (and therefore is dependent on the zero power of the reactant), the limiting factor being something other than the concentration of the reacting substance (e.g., the medicament). The limiting factor in a zero order mechanism may be, for example, the solubility of the reacting substance or the light intensity in photo chemical reactions.
As previously mentioned, however, many chemical reactions are not simple reactions of zero-, first-, or second-order, and the like, and instead comprise a combination of two or more reactions.
Moreover, other factors may influence the reaction rate, including temperature, pH, food effect variability, ions and ionic strength dependency, viscosity dependency, corrosion/erosion variability, content uniformity problems, flow and weight uniformity problems, carrying capacity and mechanical strength problems, hydrolysis, photochemical decomposition, interaction between components (such as interactions between the drug and other ingredients in the formulation, such as buffers, preservatives, and the like), the concentration of solvents of low dielectric constant (when the reaction involves oppositely charged ions), etc.
While many controlled and sustained release formulations are already known, certain soluble to highly soluble drugs present formulation difficulties when included in such formulations. Sustained release formulations with soluble drugs are susceptible to “dose dumping”. This occurrence is where the release of the active ingredient is delayed, but when release is initiated, the rate is extremely high. This elevated release rate is associated with blood plasma fluctuations which can possibly result in decreased therapeutic effect or increased toxicity. These are the same problems which sustained release formulations are supposed to solve.
Further, it is often not possible to readily predict whether a particular sustained release formulation will provide the desired sustained release for a soluble to highly soluble drug. It has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations providing the desired bioavailability of such drugs when ingested.
In order to compensate for the unpredictability associated with having a controlled release formulation provide the desired sustained release for a soluble to highly soluble drug, it is sometimes considered desirable to provide a formulation with bi-modal or multi-phasic kinetics. Bimodal or multi-phasic release may be characterized by an initial high rate followed by a slower rate as the dosage form passes the upper portion of the small intestine where absorption is maximum and finally another higher rate as the dosage form passes into the further end of the intestine where absorption is less than before.
Bimodal release is considered to be advantageous for a number of reasons, including but not limited to the fact that bimodal release allows the formulator to compensate for changing absorption rates of the medicament in the gastrointestinal tract by providing a rapid onset of action (when the formulation is located in the stomach) and compensate for relatively slow absorption by providing a relatively rapid release rate (e.g., when the formulation is located in the large intestine).
Bimodal release formulations have been provided in a number of different manners to date.
For example, International Publication Number WO/87/00044 describes therapeutic formulations which are said to have bimodal release characteristics. WO 87/00044 describes a carrier base material for therapeutically active medicaments in a solid dosage formulation that are said to produce a bimodal controlled release profile characterized by a rapid initial release of medicament followed by a substantially constant rate of release for a period of time, after which the release rate is greater than the constant rate previously observed. The carrier based material comprises bimodal hydroxypropylmethylcellulose ethers with a methoxy content of 19-30%, a hydroxy propoxy content of 4-12%, a viscosity of 40-19,000 cps, an average molecular weight of 20,000-140,000, and which demonstrates a bimodal release profile in accordance with an assay method described therein. The bimodal hydroxypropylmethylcelluloses comprise 5-99% by weight of the total formulation, depending upon the active ingredient and length of drug released desire.
A. C. Shah et al. “Gel-Matrix Systems Exhibiting Bimodal Controlled Release For Oral Drug Delivery”, Journal of Controlled Release, 9(1989), pp. 169-175, further reported that certain “types” of hydroxypropylmethylcellulose ethers are found to display a bimodal drug release profile. However, in that study, series of hydroxypropylmethylcellulose ether polymers were found to provide bimodal and non-bimodal release profiles from polymer-drug matrix tablets, which results appeared to depend upon the supplier of the polymer (and therefore upon, e.g., the method of manufacture, ionic composition, variations in the distribution of substituent groups, or distribution of molecular weight fractions).
P. Giunchedi et al., “Ketoprofen Pulsatile Absorption From ‘Multiple Unit’ Hydrophilic Matrices” International Journal of Pharmaceutics, 77(1991), pp. 177-181 described an extended release oral formulation of Ketoprofen comprising a multiple unit formulation constituted by four hydrophilic matrices of identical composition, each containing 50 mg of drug and prepared with hydroxypropylmethylcellulose (Methocel®) and placed in a gelatin capsule. Pulsatile plasma levels (2 peaks at 2nd and 8th hours after-dosing) were said to be obtained, whereas in vitro tests resulted in a fairly constant drug release.
U. Conte et al., “A New Ibuprofen Pulsed Release Oral Dosage Form”, Drug Development And Industrial Pharmacy, 15(14-16), pp 2583-2596 (1989) reported that a pulsed released pattern was obtained from a 3-layer tablet wherein two layers contained a dose of drug, and an intermediate layer acted as a control element separating the drug layers. The control element was a mixture of water-swellable polymers (hydroxypropylmethylcelluloses). An outer film of an impermeable polymer coated the tablet. A superdisintegrant (sodium starch glycolate and cross-linked polyvinyl pyrrolidone) was included in the drug layers.
K. A. Kahn et al, “Pharmaceutical Aspects And In-Vivo Performance Of Brufen Retard—An Ibuprofen SR Matrix Tablet”, Proced. Intern. Symp. Control. Rel. Bioact. Mater., 18(1991), Controlled Release Society, Inc., describes a formulation containing 800 mg of ibuprofen which is said to provide a bimodal release pattern. The release retarding agent utilized therein was xanthan gum. The ingredients were blended to the appropriate xanthan gum content, and thereafter compressed into tablets and film coated. The amount of xanthan gum included inversely affected the rate of drug release. An increase in drug particle size or quantity of film-coat per tablet did not significantly effect the rate of drug release. Although an increase in particle size of the xanthan gum caused a more pronounced burst effect, the application of the film-coat overcame this burst effect. The rapid initial release of the medicament was hypothesized to be related to changes in the formation of the gel layer, wherein larger particles gel more slowly and are sloughed off before a coherent matrix can form.
In our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, hereby incorporated by reference, we reported that a controlled release excipient which is comprised of synergistic heterodisperse polysaccharides (e.g., a heteropolysaccharide such as xanthan gum in combination with a polysaccharide gum capable of cross-linking with the heteropolysaccharide, such as locust bean gum) is capable of processing into oral solid dosage forms using either direct compression, following addition of drug and lubricant powder, conventional wet granulation, or a combination of the two. The release of the medicament from the formulations therein proceeded according to zero-order or first-order mechanisms.
Our own U.S. Pat. Nos. 5,472,711 and 5,478,574, hereby incorporated by reference, we report a formulation capable of providing multi-phasic or bi-phasic controlled release of a therapeutically active medicament in vitro by incorporating an effective amount of a pharmaceutically acceptable surfactant with the above-referenced excipient.
An example of a highly soluble drug used in the present invention is diltiazem, which is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem is widely used in the treatment of hypertension and angina. Accordingly, a great deal of attention has been given to the preparation of sustained release diltiazem which provides an acceptable release profile. For example U.S. Pat. Nos. 4,894,240 and 5,364,620 (Geoghegan, et al.) describe a diltiazem pellet formulation suitable for once daily administration. This formulation comprises a diltiazem core in association with an organic acid, surrounded by an insoluble multi-layer membrane. The membrane allows the release of diltiazem from the pellet at a rate allowing controlled absorption over a 24 hour period following administration.
Other techniques have been described in the prior art for preparing sustained release diltiazem formulations. For example, U.S. Pat. No. 5,419,917 (Chen et al.) describes a composition which controls the rate of release of diltiazem from a hydrogel using a pharmaceutically effective ionizable compound.
Another example of a highly soluble drug used in the present invention is oxybutynin. Oxybutynin is widely used in the treatment of urological disorders, e.g., hyperactive bladder. Our own U.S. Pat. No. 5,399,359 discloses an oxybutynin sustained release formulation comprising a pharmaceutically effective amount of oxybutynin dispersed within a sustained release matrix comprising a gelling agent, an effective amount of a pharmaceutically acceptable water-soluble cationic cross-linking agent which cross-links with the gelling agent when the formulation is exposed to an environmental fluid, e.g., gastrointestinal fluid, and an inert diluent.